fragile X syndrome
What is Fragile X Syndrome?
Fragile X syndrome is a condition that causes a spectrum of developmental and behavioral problems which tend to be more severe in males. The condition is also more common among men than women. It is the most common form of inherited intellectual disability.
Fragile X syndrome typically causes moderate intellectual disability in males, although the severity of intellectual impairment varies from person to person. A small number of males do not have intellectual disability, defined as an IQ below 70. About a third of women with fragile X syndrome have no cognitive impairment, while the remainder have some degree of cognitive, behavioral, or social difficulties. Some females with fragile X syndrome have mild intellectual disability.
As infants, children with fragile X syndrome may display poor muscle tone, gastric reflux, and frequent ear infections. Their motor and mental milestones, as well as their speech, tend to be delayed.
Children with fragile X syndrome often have behavioral problems such as anxiety, hyperactivity, hand-flapping, biting, and temper tantrums. About one-third of males with fragile X syndrome have autism or autism-like behavior.
In females, who often have milder symptoms, behavioral problems may appear as depression, shyness, and avoidance of social situations.
Some people with the condition have attention deficit disorder, with an inability to sustain focused attention on a specific task.
As they become adolescents and young adults, people with fragile X syndrome, particularly males, may lack impulse control, make poor eye contact, and/or be easily distracted. They often have unusual responses to being touched or to sights and sounds.
Males with fragile X syndrome often share characteristic physical features such as a long, narrow face with a prominent jaw and forehead, a large head, flexible joints, and large ears. These symptoms tend to be milder or absent in females with the condition.After puberty, males with fragile X syndrome typically have enlarged testicles.Roughly 15 percent of males and 5 percent of females with fragile X syndrome will experience seizures. While some experience heart murmurs from a condition called mitral valve prolapse, it is usually harmless and may not require treatment.
Effects of a Premutation
Men and women with a premutation (please see below for a description) do not have fragile X syndrome, but may experience certain physical symptoms. While they are intellectually normal, they are thought to be more vulnerable to anxiety and depression.
The key risks for carriers of a premutation are fragile X-associated tremor/ataxia syndrome (FXTAS) and premature ovarian failure (POF).
About 40% of men over the age of 50 with a fragile X premutation will develop FXTAS. (The percentage of women premutation carriers affected by FXTAS is unknown, but known to be lower.) FXTAS causes an inability to coordinate muscle movements (ataxia) that worsens over time, tremors, memory loss, dementia, a loss of feeling and weakness in the lower legs, and some mental and behavioral changes.
Often symptoms of FXTAS begin around age 60 with a tremor, followed several years later by ataxia. One study of 55 men with FXTAS found that from the time symptoms begin, additional life expectancy ranged from 5 to 25 years.
About 20 percent of women with a premutation experience premature ovarian failure (POF), in which their menstrual periods stop by age 40. Only 5 to 10 percent of women with POF will be able to have children. One study found that 21 percent of women with a premutation experienced POF, compared to 1 percent in the general population. In general, women with premutations larger than 80 repeats (see below for an explanation) were at lower risk for POF when compared to women with smaller premutations. Women with full mutations are not at increased risk for POF.
How is Fragile X Syndrome inherited?
Fragile X syndrome is inherited in a complex way that is different from many other genetic diseases. If you have any questions about fragile X syndrome, a healthcare professional can help explain this condition and your risk of transmitting it to the next generation.
Fragile X syndrome is inherited in an X-linked dominant pattern. The gene associated with the disease is located on the X chromosome. The X and Y chromosomes determine gender. Women have two X chromosomes (XX) while men have one X chromosome and one Y chromosome (XY). Girls receive one X chromosome from their mother and one from their father. Boys receive one X chromosome from their mother and a Y chromosome from their father. Typically, unaffected female full mutation carriers of fragile X syndrome are at risk of transmitting the condition to their children.
Fragile X syndrome is among a group of diseases called "trinucleotide repeat disorders." At its most basic level, these diseases are caused by a sequence of DNA that is repeated over and over in the same gene. While everyone has these repeats, it is the number of times that it is repeated which determines whether or not a person has the disease or can pass it on to future generations.
Fragile X syndrome is caused by a mutation in the FMR1 gene, which is located on the X chromosome. This gene contains a segment of DNA called the "CGG repeat," in which a particular section of DNA is repeated a certain number of times in a row. By counting the number of CGG repeats that each parent has, we can determine the likelihood that his or her child will have fragile X syndrome.
The CGG repeat in the FMR1 gene falls into one of four categories, each of which are explained below:
|Category||FMR1 CGG repeat size|
|Normal||5 to 44 repeats|
|Premutation||55 to 200 repeats|
|Full mutation||More than 200 repeats|
A FMR1 gene with 5 to 44 CGG repeats is considered normal. Someone with this size FMR1 CGG repeat is very unlikely to pass on fragile X syndrome to his or her children. You can think of these genes as "stable": they usually pass from parent to child with the same number of repeats. For example, if the parent's gene has 15 CGG repeats, his or her child is also very likely to have a gene with 15 CGG repeats.
Someone with 45 to 54 repeats is not at substantial risk for passing onfragile X syndrome to his or her child, however the number of repeatstransmitted to the next generation may increase slightly. For example, aparent with 45 CGG repeats could have a child with 50 CGG repeats. If thenumber of repeats continues to increase in subsequent generations, futuregenerations (i.e. grandchildren or great-grandchildren) may be at risk forinheriting fragile X.
Those with 55 to 200 CGG repeats have a "premutation." They themselves do not have symptoms of fragile X syndrome, although they are at increased risk for FXTAS and POF (see above). However, depending which parent has the premutation, future children may be at risk.
You can think of premutations as "unstable." When passed from mother to child, premutations may expand into full mutations in the child. If the number of CGG repeats exceeds 200 in the child, that child will have fragile X syndrome.
Men who have a premutation will pass on that premutation unchanged to theirdaughters, who would then also have a premutation. While a daughter is notat risk for fragile X syndrome, her future children may be at risk. Also,daughters of men with a premutation will be at risk for POF. (Men pass Ychromosomes to their sons, so this disease is not transmitted from father toson.)
Someone with more than 200 repeats has a full mutation, and likely has symptoms of fragile X syndrome.
Because symptoms of the disease are often milder in women, some women with a full mutation can have children. Those children each have a 50% chance of having fragile X syndrome. Men who have a full mutation generally do not reproduce.
Full mutations cause the FMR1 gene to malfunction, shutting down its ability to produce a protein called fragile X mental retardation 1 protein. The function of this protein is not well understood, but scientists believe that it plays a role in the proper functioning of the nervous system.
If a parent has a mutation or premutation, what is the risk that his or her child will develop fragile X syndrome?
If a mother has a full mutation, 50% of her children will have fragile X syndrome. Men who have full mutations typically do not reproduce.
Premutations are more complicated. When the parent has a premutation, the risk of a child developing fragile X syndrome depends on the answers to several questions, each of which are detailed below:
- Which parent has the premutation?
- Will the child inherit the gene containing the premutation?
- Will the premutation expand to a full mutation?
Which parent has the premutation?
If a women is a premutation carrier, then she is at risk of having children with fragile X syndrome. Premutations inherited from the mother are unstable and may expand to become full mutations in the child.
Premutations pass more or less identically from father to child; the CGG repeats do not expand in number. Therefore, men with premutations are not at risk of having children with fragile X syndrome.
Will the child inherit the premutation?
If the father has a premutation on his X chromosome, all of his daughters will have that same premutation. These daughters are generally not at risk of having fragile X syndrome themselves, but their future children (the grandchildren of the original premutation carrier) will be at risk. Fathers pass a Y chromosome to their sons instead of an X, so fragile X premutations cannot be passed from father to son.
If the mother has a premutation on one of her X chromosomes, 50% of her children will inherit that abnormal gene and 50% will inherit the normal gene. Only children who inherit the abnormal gene would be at risk for fragile X syndrome.
Will the premutation expand to a full mutation?
If a mother has a gene with a premutation and that abnormal gene gets passed to her children, there are two possibilities:
- The premutation does not expand beyond 200 repeats and remains a premutation in the child. That child has no symptoms of fragile X syndrome, but may experience FXTAS (male) or POF (female) as adults.
- The premutation expands into a full mutation, causing fragile X syndrome.
The greater the number of CGG repeats a woman has, the more unstable the gene is and the more likely it will expand to a full mutation in her children. The smallest allele yet observed to expand to a full mutation in a single generation is 56 repeats.
|Number of Maternal Premutation CGG Repeats||Percentage (total women) which expanded to full mutations|
Nolin SL, Brown WT, Glicksman A, Houck GE Jr, Gargano AD, Sullivan A, et al. (2003). Expansion of the fragile X CGG repeat in females with premutation or intermediate alleles. American Journal of Human Genetics, 72(2):454-64.
Nolin SL, Glicksman A, Ding X, Ersalesi N, Brown WT, Sherman SL, Dobkin C. (2011). Fragile X analysis of 1112 prenatal samples from 1991 to 2010. Prenatal Diagnosis, 31(10):925-31.
How common is Fragile X Syndrome?
An estimated 1 in 4000 males and 1 in 8000 females is affected by fragile X.
Based on a review of the literature and Counsyl's internal data, approximately 1 in 225 women carries a premutation and 1 in 45 carries an intermediate allele.
How is Fragile X Syndrome treated?
There is no cure for fragile X syndrome, however children with the condition can be treated and supported in many ways, depending on their particular symptoms and the severity of those symptoms. They may benefit from educational support like early developmental intervention, special education classes in school, speech therapy, occupational therapy, and behavioral therapies. A physician may also prescribe medication for their behavioral issues such as aggression, anxiety, or hyperactivity.
A small number of these children experience seizures which can be controlled with medication. While some experience heart murmurs from a condition called mitral valve prolapse, it is usually harmless and may not require treatment.
What is the prognosis for a person with Fragile X Syndrome?
While many of the children with fragile X syndrome have learning and behavioral problems, they generally do not have major medical problems and can live a normal life span.